chr11-67401230-A-G

Variant names:

• chr11-67401230-A-G
• ENST00000312989.11:c.58T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000312989.11(PPP1CA):​c.58T>C​(p.Ser20Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,458,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: PPP1CA ENST00000312989.11 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.69
• Publications: 0 publications found

Genes affected

PPP1CA (HGNC:9281): (protein phosphatase 1 catalytic subunit alpha) The protein encoded by this gene is one of the three catalytic subunits of protein phosphatase 1 (PP1). This broadly expressed gene encodes the alpha subunit of the PP1 complex that associates with over 200 regulatory proteins to form holoenzymes which dephosphorylate their biological targets with high specificity. PP1 is a serine/threonine specific protein phosphatase known to be involved in the regulation of a variety of cellular processes, such as cell division, glycogen metabolism, muscle contractility, protein synthesis, and HIV-1 viral transcription. Increased PP1 activity has been observed in the end stage of heart failure. Studies suggest that PP1 is an important regulator of cardiac function and that PP1 deregulation is implicated in diabetes and multiple types of cancer. Three alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2020]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07371962).
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1CA	NM_002708.4	c.56-31T>C		intron_variant	Intron 1 of 6	ENST00000376745.9	NP_002699.1
PPP1CA	NM_001008709.2	c.58T>C	p.Ser20Pro	missense_variant, splice_region_variant	Exon 2 of 7		NP_001008709.1
PPP1CA	NM_206873.2	c.56-311T>C		intron_variant	Intron 1 of 5		NP_996756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1CA	ENST00000376745.9	c.56-31T>C		intron_variant	Intron 1 of 6	1	NM_002708.4	ENSP00000365936.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1458476 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 724884

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1109706

Other (OTH) AF: 0.0000166 AC: 1 AN: 60226

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.58T>C (p.S20P) alteration is located in exon 2 (coding exon 2) of the PPP1CA gene. This alteration results from a T to C substitution at nucleotide position 58, causing the serine (S) at amino acid position 20 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.54
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.99	T
PhyloP100		-3.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.0080
Sift	Benign	0.28	T
Sift4G	Benign	0.21	T
Vest4		0.091
MutPred		0.43		Loss of helix (P = 0.0196);
MVP		0.12
MPC		0.050
ClinPred		0.043	T
GERP RS		-0.18
PromoterAI		0.086	Neutral
gMVP		0.89
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr11-67168701;